Antibody (Ab)-mediated bacterial opsonization is essential for protective immunity against Streptococcus pneumoniae in humans, as attested to by the frequent occurrence of invasive pneumococcal disease (IPD) in patients with B cell primary immunodeficiencies (PIDs) and impaired Ab response to pneumococcal capsular glycansi'2. Carrying forward the theme of B cell immunity in this Program Project, we aim to decipher new molecular genetic bases of three otherwise distinct PIDs sharing both impaired Ab response to glycans and predisposition to IPD, (i) anhidrotic ectodermal dysplasia vdth immunodeficiency (EDA-ID), (ii) specific antibody deficiency (SPAD) and IgGa deficiency (IgG2D), and (iii) common variable immunodeficiency (CVID). EDA-ID is a rare syndromic PID of childhood, associated with recurrent IPD and abolished Ab response to glycans3'4, due in most cases to mutations in NEMO and IKBQ, which underlie, respectively, X- linked recessive (XR) and autosomal dominant (AD) formsS'^. SPAD and IgG2D confer a more selective impairment of Ab response to glycans, which may lead to IPD^'S, and are rarely caused by mutations in the IgG2 locus itself, with autosomal recessive (AR) inheritance^''^. CVID is more common, associated with a global decrease in IgG levels, impaired Ab response to glycans and IPD in adults'3, and rarely caused by AR mutations in ICOS, TACI, BAFF-R, CD19, CD20 and CDSi's-ie. We hypothesize that genetically unexplained EDA-ID, SPAD/IgG2D, or CVID result from novel inborn errors. We thus aim to decipher novel IPD- predisposing single-gene inborn errors of Ab-mediated immunity to glycans in patients with these PIDs. We will use genome-wide approaches, taking advantage of the recent advent of whole-exome and -genome sequencing, which have been pioneered in the lab for human PIDs'^.is. The immunological consequences of the mutant alleles v\all be studied in collaboration with other teams of this project. Our preliminary data are exciting, as we recently identified new genetic etiologies of EDA-ID (mutations in P2Y4) and SPAD/IgG2D (mutations in RBCKi and TIFA). We also obtained our first whole-exome data for young subjects with CVTD. This project will result in the discovery of new genetic etiologies of three distinct PIDs sharing impaired Ab responses to glycans and predisposition to IPD. The immunological implications of this study are important, as it will shed a new light onto the genetic control of human Ab responses to glycans and protective immunity to pneumococcus. The clinical implications are equally critical, as our results will provide families with genetic counseling and pave the way for investigation of the genetic basis of IPD and B cell PIDs in other patients. RELEVANCE (See instructions): Impaired antibody (Ab) response to pneumococcus often results in invasive pneumococcal disease (IPD), sue! as septicemia or meningitis. In most patients wdth IPD and impaired Ab response to pneumococcus, the illnes; is thought to be genetically determined, but there is no known genetic underlying anomaly. We intend tc decipher the molecular genetic basis of three conditions associated wdth impaired Ab to pneumococcus anc IPD.